PROJECT SUMMARY/ABSTRACT: Overall Over 90% of cancer related mortality is linked to invasive and metastatic spread of cancer cells from the primary tumor. This spread can be catastrophically fast in the cases of particularly aggressive, high grade melanomas and gliomas (i.e., glioblastoma multiforme (GBM)), leading to uniformly poor prognosis and short life expectancy in these cancers. In spite of the crucial importance of invasive cancer phenotype, we still have only fragmentary knowledge and understanding of the mechanisms leading to transition from proliferative to aggressive, migratory behavior of cancer cells (referred here as the P-A phenotypic switch). Increasing evidence suggests that this switch is a reflection of inherent capacity of cancer cells to adopt both proliferative and migrator phenotypes, with the probability and rate of switching between these two phenotypes controlled by the cell genome, environmental conditions and cell-cell interactions. To address the problem of regulation of invasive cancer spread and, more specifically the P-A phenotypic switch, we propose to establish the Yale Cancer Systems Biology Center (Y-CSBC). The Center will based on the existing organization and infrastructure of the recently founded Yale Systems Biology Institute (YSBI) on the Yale West Campus, leveraging the extensive existing shared resources and juxtaposition of the labs within the same recently renovated, state of the art research space. The Center will bring together researchers from 7 Yale departments based at Yale schools of Arts and Science, Engineering and Applied Science and Medicine and Emory University, in close collaboration with Yale Cancer Institute (physically adjacent to YSBI), Yale Cancer Center, Yale skin cancer SPORE, and Yale Neurosurgery department. The work at the proposed Center will be initially based on the Proposed tightly knit two Research Projects and two support shared resource Cores, initially focused on the analysis of glioblastoma and melanoma cells, and normal cells of various species modeling invasive growth behavior and phenotypic switching. With time, the emphasis on these two cancers may broaden with new members expanding the scope and the aims. The proposed research already reflects the diversity and innovative nature of the work pursued by the participating labs within YSBI and collaborative labs, with the combination of techniques and approaches as diverse as synthetic biology, nano-scale bioengineering, evolutionary biology, high throughput genomics, mathematical modeling, novel animal models, all combined into a integrated research program. The work will be supported by the Administrative Core and the results disseminated through various mechanisms mediated by the Outreach and Education Core. The orthogonal and unconventional approaches proposed in the application and characteristic of the highly collaborative use of cutting edge, innovative approaches, many of which are being pioneered here, will provide an opportunity to advance our understanding of the molecular networks controlling invasive, aggressive cancer spread and lead to new approaches to controlling and treating highly invasive and metastatic malignancies.